Hypoplastic Left Heart Syndrome (HLHS) is the most common form of severe congenital heart disease and is the leading cause of cardiovascular death in infancy. HLHS comprises a spectrum of congenital malformations characterized by severe underdevelopment of all left-sided heart structures including a diminutive left ventricle (LV). This results in a univentricular circulation with the morphologic right ventricle (RV) servin as the pump to both the systemic and pulmonary circulations. This defect is universally fatal without intervention and although outcomes are improving, HLHS remains a devastating diagnosis with one-year survival rates of only 40-60%. Not surprisingly, failure of the single RV is both a common cause of death and indication for a heart transplant in infants and children with HLHS. Historically, pharmacologic treatment of heart failure in the pediatric population has largely been extrapolated from the adult heart failure experience and treatment guidelines are based primarily on expert consensus. Importantly two recent clinical trials have demonstrated that children with a systemic right ventricle (ie HLHS) do not receive any clinical benefit from either enalapril or carvedilol therapy over placebo. This evidence suggests that: [1] continued extrapolation of adult data as the basis for treatment of heart failure in children is not appropriate, [2] ventricular morphology and complex congenital heart disease are important considerations in heart failure treatment and [3] identification of novel therapeutic targets are necessary to improve outcomes in this vulnerable population. Histone deacytelases (HDACs) are enzymes that deacetylate lysine on histone and non-histone proteins and have been linked to many different processes in the failing heart. The importance of epigenetic regulation of cardiac adaptation is evident in some animal models of heart failure, where HDAC inhibitors block pathologic hypertrophy and fibrosis while improving cardiac function. The role of HDACs in human heart failure is incompletely understood, and has never been investigated in pediatric heart failure or in congenital heart disease. The central hypothesis of this proposal is that HDACs play a role in mediating pathologic adaptation of a right ventricle exposed to chronic hypoxia and pressure overload. Therefore the purpose of the current proposal is to use our existing pediatric heart tissue bank to determine the expression and catalytic activity of specific HDAC isoforms in the right ventricular myocardium of children with HLHS. In addition, we aim to characterize the role of specific HDAC isoforms and HDAC-inhibitor treatment on pathologic remodeling of the right ventricle in hypoxic neonatal rats (as a model of HLHS). Modulation of HDAC activity, given the distal site of action in the signaling pathway, could have unique therapeutic potential in RV failure in HLHS.

Public Health Relevance

Congenital heart defects are the most common type of birth defect and many of these lesions are associated with abnormal right ventricular function. The changes that occur in the hearts of children with congenital heart disease are poorly understood. The current proposal will improve our understanding of right ventricular adaptation in children and investigates a novel therapeutic target that could lead to improved medical treatment options for this vulnerable population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL113846-01A1
Application #
8445748
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Burns, Kristin
Project Start
2013-01-15
Project End
2014-11-30
Budget Start
2013-01-15
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$244,586
Indirect Cost
$82,357
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045